Tularemia vaccine development: paralysis or progress?

Abstract

Francisella tularensis (Ft) is a gram-negative intercellular pathogen and category A biothreat agent. However, despite 15 years of strong government investment and intense research focused on the development of a US Food and Drug Administration-approved vaccine against Ft, the primary goal remains elusive. This article reviews research efforts focused on developing an Ft vaccine, as well as a number of important factors, some only recently recognized as such, which can significantly impact the development and evaluation of Ft vaccine efficacy. Finally, an assessment is provided as to whether a US Food and Drug Administration-approved Ft vaccine is likely to be forthcoming and the potential means by which this might be achieved.

Differential Cultivation of Francisella tularensis Induces Changes in the Immune Response to and Protective Efficacy of Whole Cell-Based Inactivated Vaccines

“…The latter was associated with differential expression of capsular polysaccharides, the presence of capsule specific Ab, splenic IL-17 and IFN-γ production, and multifunctional CD4+ T cell responses (31). We have also observed differential protective efficacy of BHI- and MHB-grown live Ft LVS vaccine, where BHI-grown Ft LVS exhibited better protection against lethal infection with Ft SchuS4 (32). This contrasting observation may be due to the distinct immunological requirements for protection against Ft LVS and Ft SchuS4 or live versus inactivated vaccine.…”

Evaluation of Francisella tularensis ΔpdpC as a candidate live attenuated vaccine against respiratory challenge by a virulent SCHU P9 strain of Francisella tularensis in a C57BL/6J mouse model

“…However, 100% protection against F. tularensis type A strains via vaccination has been difficult to achieve . Recent reports indicate that antibodies contribute to protection against F. tularensis LVS (Type B) challenge, but the importance of antibodies to F. tularensis Schu S4 (Type A) challenge is more controversial . In this study, antibody responses against F. tularensis were well established in mice immunized s.c. with Δ pdpC (Fig.…”

“…Thus, investigation of a novel vaccine against tularemia has remained a critical research goal in recent years, the aim being to develop a fully protective attenuated vaccine for which safety concerns have been eliminated or further minimized. Numerous live attenuated mutants derived from LVS and the virulent Schu S4 strain have been developed .…”

“…It has been reported that antibodies against F. tularensis may offer a considerable survival advantage in patients with respiratory tularemia because these antibodies have been shown to inhibit bacterial spread from the lungs to other organs . However, 100% protection against F. tularensis type A strains via vaccination has been difficult to achieve . Recent reports indicate that antibodies contribute to protection against F. tularensis LVS (Type B) challenge, but the importance of antibodies to F. tularensis Schu S4 (Type A) challenge is more controversial .…”

“…C57BL/6 and BALB/c mice are often used as animal models of tularemia as well as for studies on F. tularensis vaccine development. The genetic background of individual strains of mice often significantly affects the immune response and survival rates in murine models of infectious diseases and vaccination . It is known that C57BL/6 mice are more susceptible to F. tularensis infection and that they exhibit more severe symptoms of tularemia than BALB/c mice .…”